Systemic metabolic defects caused by epidermal EGFR-deficiency

The epidermal growth factor receptor (EGFR) is an important regulator of epidermal function and homeostasis. This is evidenced by the fact that epidermal deletion of Egfr in mice (Egfrep ) leads to perturbed skin differentiation. Interestingly, mice lacking Egfr in the epidermis also show severely reduced growth and die during the first three weeks of life. To better understand the growth defect of Egfr ep mice, we have started to examine the possibility that changes in the metabolism of these animals might be causally involved. Indeed, we have found that epidermal loss of Egfr- signaling results in severely perturbed glucose metabolism and insulin levels in the blood. Importantly, gene expression patterns of metabolic regulators in livers of Egfr ep mice indicate that glucose metabolism is deregulated already a few days after birth. In addition, the "starvation-signal" fibroblast growth factor 21 (Fgf21) is highly expressed in livers of these animals. To test whether excessive feeding protects Egfr ep animals from death, we crossed these mice into a leptin-deficient background and found that this fully rescues the lethality caused by epidermal Egfr-deficiency. Furthermore, animal growth as well as glucose and insulin levels are improved in such animals, strongly suggesting that the lethality caused by epidermal Egfr-deficiency stems from systemically deregulated metabolism. Searching for potential molecular mediators of this metabolic dysfunction, we found that insulin-like growth factor binding protein 2 (Igfbp2), a regulator of glucose metabolism, is massively over- expressed in the epidermis of Egfr ep mice, which in turn leads to high serum levels of Igfbp2. High systemic levels of Igfbp2 are associated with impaired growth in humans and mice, suggesting that the lack of epidermal repression of Igfbp2 by Egfr might be the cause for the systemic defects in Egfr ep mice. Combining various, in part novel, genetic mouse models with state of the art analyses of metabolism, we aim at a precise understanding of the systemic metabolic defect of mice lacking Egfr in the epidermis and to answer the question to what extent this is caused by Igfbp2 over-expression. This will be achieved by a detailed analysis of glucose metabolism and liver function in mice which lack Egfr in the epidermis and in animals in which Igfbp2 expression can be induced specifically in this organ. In addition, we will monitor in living mice energy expenditure by indirect calorimetry and body composition via magnetic resonance imaging (MRI). We will furthermore address why leptin-deficiency rescues animals from the consequences of epidermal Egfr-deficiency, focusing on a potential interplay of Igfbp2 and leptin in the regulation of glucose metabolism. Finally, we will test whether Egfr-regulated Igfbp2 expression can impact on complex metabolic diseases such as obesity associated insulin resistance and diabetes. Ultimately, the experiments presented in this proposal will provide new insights into the complex consequences of epidermal Egfr-deficiency, which might also be relevant for cancer patients treated with Egfr inhibitors. Furthermore, they will lead to a better understanding of the role of the skin in the regulation of systemic metabolism.